CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER: 201444Orig1s000

PROPRIETARY NAME REVIEW(S)

Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology

Date: October 8, 2010 Application NDA# 201444 Type/Number:

Through: Todd Bridges, RPh, Team Leader Denise Toyer, PharmD, Deputy Director Carol Holquist, RPh, Director Division of Medication Error Prevention and Analysis (DMEPA) From: Denise V. Baugh, PharmD, BCPS, Safety Evaluator Division of Medication Error Prevention and Analysis (DMEPA) Subject: Proprietary Name Review Drug Name(s): Nithiodote

1 vial of Sodium Nitrite Injection, USP, 300 mg/10 mL (30 mg/mL)

1 vial of Sodium Thiosulfate Injection, USP, 12.5 grams/50 mL (250 mg/mL)

Applicant: Hope Pharmaceuticals, Inc. OSE RCM #: 2010-1360 *** Note: This review contains proprietary and confidential information that should not be released to the public.***

CONTENTS

EXECUTIVE SUMMARY...... 2 1 BACKGROUND...... 2 1.1 Introduction...... 2 1.2 Regulatory History...... 2 1.3 Product Information ...... 2 2 METHODS AND MATERIALS ...... 3 2.1 Search Criteria...... 3 2.2 FDA Prescription Analysis Studies...... 4 2.3 Adverse Event Reporting System (AERS) ...... 4 3 RESULTS...... 5 3.1 Database and Information Sources...... 5 3.2 CDER Expert Panel Discussion...... 5 3.3 FDA Prescription Analysis Studies...... 5 3.4 AERS Cases...... 5 3.5 Safety Evaluator Risk Assessment...... 5 3.6 Comments from the Division of Anesthesia and Analgesia Products (DAAP)...... 6 4 DISCUSSION ...... 6 4.1 Promotional Assessment...... 6 4.2 Safety Assessment...... 6 5 CONCLUSIONS AND RECOMMENDATIONS...... 6 5.1 Comments To The Applicant...... 7 6 REFERENCES...... 8 APPENDICES...... 10

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EXECUTIVE SUMMARY

This review summarizes the Division of Medication Error Prevention and Analysis (DMEPA) proprietary name risk assessment for Nithiodote for co-packaged Sodium Nitrite Injection, USP (30 mg/mL) and Sodium Thiosulfate Injection, USP (250 mg/mL). Our evaluation did not identify concerns that would render the name unacceptable based on the product characteristics and safety profile known at the time of this review. Thus, DMEPA finds the proposed proprietary name, Nithiodote, acceptable for this product (See Section 4 for full discussion). DMEPA considers this a final review, however, if approval of the NDA is delayed beyond 90 days from the date of this review, the proposed proprietary name, Nithiodote, must be re-evaluated. Additionally, if any of the proposed product characteristics as stated in this review are altered, DMEPA rescinds this finding and the name must be resubmitted for review. The conclusions upon re-review are subject to change.

1 BACKGROUND

1.1 INTRODUCTION This review responds to a request from Hope Pharmaceuticals, Inc., submitted September 8, 2010, to evaluate the proposed proprietary name, Nithiodote, regarding promotional and potential name confusion with other proprietary or established drug names based on the product characteristics provided by the Applicant. The Applicant also submitted container labels and carton labeling which will be reviewed under separate cover (OSE Review #2010-1361).

1.2 REGULATORY HISTORY This NDA is a 505(b)(2) submission for a cyanide antidote containing one vial of sodium nitrite and one vial of sodium thiosulfate. The reference listed drug (RLD) for Nithiodote is sodium thiosulfate injection, USP (NDA # 020166), which was approved on February 14, 1992, (applicant was U.S. Army) to be given with sodium nitrite injection. However, the sodium thiosulfate injection drug product is no longer commercially available and there are no FDA- approved sodium nitrite and sodium thiosulfate products currently marketed in the United States. The only other available treatment for cyanide poisoning is Cyanokit (hydroxocobalamin) for injection (NDA# 022041) which was approved December 15, 2006.

1.3 PRODUCT INFORMATION Nithiodote, which is indicated for the treatment of (b) (4) cyanide poisonings, is composed of one vial of sodium thiosulfate injection and one vial of sodium nitrite injection co- packaged. The proposed dosing regimen is: 1) Inject intravenously 10 mL of a 3% solution (300 mg) of sodium nitrite at the rate of 2.5 to 5 mL/minute. The recommended dose of a 3% solution of sodium nitrite for children is 6 to 8 mL/m2 of body surface area (approximately 0.2 mL/kg of body weight) not to exceed (NTE) 10 ml of a 3% solution (300 mg). 2) Immediately thereafter, inject 50 mL of a 25% solution (12.5 g) of sodium thiosulfate for adults. The recommended dose of a 25% solution of sodium thiosulfate for children is 30 to 40 mL/m2 of body surface area (approximately 1 mL/kg of body weight) but

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dosage should not exceed 50 mL of a 25% solution (12.5 g). The same needle and vein may be used. Personnel should acquire some skill in the proper method of administering sodium nitrite and sodium thiosulfate prior to an emergency. Cyanide poisoning is fatal. The patient should be watched closely for at least 24 to 48 hours. If signs of poisoning reappear, one-half of the original doses of both sodium nitrite and sodium thiosulfate should be repeated. Even if the patient seems perfectly well, the medication may be given for prophylactic purposes 2 hours after the first injections. If respiration has ceased but the pulse is palpable, artificial respiration should be applied at once. The purpose is not to revive per se, but to keep the heart beating. Each carton of Nithiodote consists of: • one 10 ml glass vial of Sodium Nitrite Injection 30 mg/mL (containing 300 mg of sodium nitrite); • one 50 mL glass vial of sodium thiosulfate injection 250 mg/mL (containing 12.5 grams of sodium thiosulfate); and • one package insert. The kit should be stored at controlled room temperature between 20 C and 25 C (68 F to 77 F); excursions permitted to 15 C to 30 C (59 F to 86 F). Protect from light. Do not permit to freeze.

2 METHODS AND MATERIALS Appendix A describes the general methods and materials used by the Division of Medication Error Prevention and Analysis (DMEPA) when conducting a proprietary name risk assessment for all proprietary names. Sections 2.1, 2.2 and 2.3 identify specific information associated with the methodology for the proposed proprietary name, Nithiodote.

2.1 SEARCH CRITERIA For this review, particular consideration was given to drug names beginning with the letter ‘E’ when searching to identify potentially similar drug names, as 75% of the confused drug names reported by the USP-ISMP Medication Error Reporting Program involve pairs beginning with the same letter.1,2 To identify drug names that may look similar to ‘Nithiodote’, the DMEPA staff also considers the orthographic appearance of the name on lined and unlined orders. Specific attributes taken into consideration include the length of the name (ten letters), upstrokes (5, one capital N, two lower case ‘t’, one lower case ‘h’, and one lower case ‘d’), down-strokes (none), dotted letters (2, lower case ‘i’) and cross-strokes (2, lower case ‘t’). Additionally, several letters in Nithiodote may be vulnerable to ambiguity when scripted (see Appendix B). As such, the DMEPA staff also considers these alternate appearances when identifying drug names that may look similar to Nithiodote. When searching to identify potential names that may sound similar to Nithiodote, the DMEPA staff searches for names with similar number of syllables (four), stresses (ni-THI-o-dote,

1 Institute for Safe Medication Practices. Confused Drug name List (1996-2006). Available at http://www.ismp.org/Tools/confuseddrugnames.pdf 2 Kondrack, G and Dorr, B. Automatic Identification of Confusable Drug Names. Artificial Intelligence in Medicine (2005)

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the verbatim terms “Hydroxoco%” and “Cyanok%” using the high level group terms (HLGT) “medication errors” and “product quality issues”.

3 RESULTS

3.1 DATA BASE AND INFORMATION SOURCES The DMEPA safety evaluator searches yielded a total of eighteen names as having some similarity to the name Nithiodote. Fourteen of the 18 names (Acetadote, Methadone, Nitrostat, Lithionate, Metadate CD, Metadate ER, Methionine, Nitazoxanide, Nizatidine, Miltefosine, Vilazodone, Nilutamide, Nicorette, and Norethindrone) were thought to look like Nithiodote. One name (Sethotope) was thought to sound like Nithiodote and three names (Methadose, Nithiodote, and Ethiodol) were thought to look and sound like Nithiodote. A search of the United States Adopted Name stem list on August 26, 2010, did not identify any United States Adopted Names (USAN) stem within the proposed name, Nithiodote.

3.2 CDER EXPERT PANEL DISCUSSION The Expert Panel reviewed the pool of names identified by DMEPA safety evaluators (See Section 3.1 above) and noted no additional names thought to have orthographic or phonetic similarity to Nithiodote. DDMAC had no concerns regarding the proposed name from a promotional perspective, and did not offer any additional comments relating to the proposed name.

3.3 FDA PRESCRIPTION ANALYSIS STUDIES A total of 30 practitioners responded. Four (n = 4) respondents interpreted the name correctly as ‘Nithiodote’, with correct interpretation mostly occurring in the written inpatient studies. The remainder of the responses misinterpreted the drug name. Common misinterpretations included the second ‘i’ mistaken for an ‘r’ and the second ‘o’ mistaken for an ‘a’. Additionally, two respondents in the verbal study misinterpreted the proposed name, Nithiodote, as “Ethiodate”, which is similar to the currently marketed product, Ethiodol. Another respondent in the verbal study misinterpreted the proposed name, Nithiodote, as “Methydate”, which is similar to the currently marketed product, Metadate. Both of these names were identified in our database search and therefore have been included in this review.

3.4 AERS CASES Both searches did not result in any reports of medication errors that would translate to the use of this drug product, Nithiodote.

3.5 SAFETY EVALUATOR RISK ASSESSMENT Independent searches by the primary Safety Evaluator identified 8 additional names (Menadione, Methimazole, Metaxalone, Metromidol, Naltrexone, Nefazodone, Nutrestore, and MultiHance) thought to look similar to Nithiodote and represent a potential source of drug name confusion. As such, a total of 26 names were further analyzed to determine if the drug names could be confused with Nithiodote and if the drug name confusion would likely result in a medication error in the usual practice setting. Failure Mode and Effects Analysis was then applied to determine if

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the proposed name, Nithiodote, could potentially be confused with any of the 26 names and lead to medication errors.

3.6 COMMENTS FROM THE DIVISION OF ANESTHESIA AND ANALGESIA PRODUCTS (DAAP)

3.6.1 Midpoint of Review On September 10, 2010, DMEPA notified DAAP via email that we find the name Nithiodote acceptable. Per email correspondence from DAAP on September 10, 2010, they had no objection to the name and did not have any additional comments.

4 DISCUSSION This proposed name, Nithiodote, was evaluated from a safety and promotional perspective based on the product characteristics provided by the Applicant. Furthermore, input from pertinent disciplines involved with the review of this application was considered accordingly.

4.1 PROMOTIONAL ASSESSMENT DDMAC had no concerns regarding the proposed name from a promotional perspective, and did not offer any additional comments relating to the proposed name. The Division of Anesthesia and Analgesia Products and DMEPA concurred with the promotional assessment.

4.2 SAFETY ASSESSMENT DMEPA identified and evaluated 26 names for their potential similarity to the proposed name, Nithiodote. No other aspects of the name were identified as additional sources of error. Six of the 26 names were eliminated for the reasons described in Appendices D through G. Specifically, two of the names lacked convincing orthographic and/or phonetic similarities, one name is the subject of this review, one name was unlikely to be written on a prescription, and two products are no longer available and lack a generic equivalent. Failure Mode and Effects Analysis was applied to determine if the proposed name, Nithiodote, could potentially be confused with the remaining 20 names and lead to medication errors. This analysis determined that the name similarity between Nithiodote and the identified names was unlikely to result in medication errors with any of the 20 products identified for the reasons presented in Appendices H through J.

5 CONCLUSIONS AND RECOMMENDATIONS The Proprietary Name Risk Assessment findings indicate that the proposed name, Nithiodote, is not vulnerable to name confusion that could lead to medication errors, nor is it considered promotional. Thus, the Division of Medication Error Prevention and Analysis (DMEPA) has no objection to the proposed proprietary name, Nithiodote, for this product at this time. However, if any of the proposed product characteristics as stated in this review are altered prior to approval of the product, DMEPA rescinds this Risk Assessment finding and the name must be resubmitted for review. In the event that our Risk Assessment finding is rescinded, the evaluation of the name on resubmission is independent of the previous Risk Assessment, and as such, the conclusions on re-review of the name are subject to change. Furthermore, if the approval of this application is delayed beyond 90 days from the signature date of this review, the proposed name must be resubmitted for evaluation.

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5.1 COMMENTS TO THE APPLICANT We have completed our review of the proposed proprietary name, Nithiodote, and have concluded that the name is acceptable. If any of the proposed product characteristics are altered prior to approval of the marketing application, the proprietary name should be resubmitted for review. The conclusions upon re- review are subject to change.

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6 REFERENCES

1. Micromedex Integrated Index (http://csi.micromedex.com) Micromedex contains a variety of databases covering pharmacology, therapeutics, toxicology and diagnostics.

2. Phonetic and Orthographic Computer Analysis (POCA) POCA is a database which was created for the Division of Medication Error Prevention and Analysis, FDA. As part of the name similarity assessment, proposed names are evaluated via a phonetic/orthographic algorithm. The proposed proprietary name is converted into its phonemic representation before it runs through the phonetic algorithm. Likewise, an orthographic algorithm exists which operates in a similar fashion.

3. Drug Facts and Comparisons, online version, St. Louis, MO (http://factsandcomparisons.com) Drug Facts and Comparisons is a compendium organized by therapeutic course; it contains monographs on prescription and OTC drugs, with charts comparing similar products.

4. FDA Document Archiving, Reporting & Regulatory Tracking System [DARRTS] DARRTS is a government database used to organize Applicant and Sponsor submissions as well as to store and organize assignments, reviews, and communications from the review divisions.

5. Division of Medication Errors Prevention and Analysis proprietary name consultation requests This is a list of proposed and pending names that is generated by the Division of Medication Error Prevention and Analysis from the Access database/tracking system.

6. Drugs@FDA (http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm) Drugs@FDA contains most of the drug products approved since 1939. The majority of labels, approval letters, reviews, and other information are available for drug products approved from 1998 to the present. Drugs@FDA contains official information about FDA approved brand name, generic drugs, therapeutic biological products, prescription and over- the-counter human drugs and discontinued drugs and “Chemical Type 6” approvals.

7. Electronic online version of the FDA Orange Book (http://www.fda.gov/cder/ob/default.htm) The FDA Orange Book provides a compilation of approved drug products with therapeutic equivalence evaluations.

8. U.S. Patent and Trademark Office (http://www.uspto.gov) USPTO provides information regarding patent and trademarks.

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9. Clinical Pharmacology Online (www.clinicalpharmacology-ip.com) Clinical Pharmacology contains full monographs for the most common drugs in clinical use, plus mini monographs covering investigational, less common, combination, nutraceutical and nutritional products. It also provides a keyword search engine.

10. Data provided by Thomson & Thomson’s SAEGIS ™ Online Service, available at (www.thomson-thomson.com) The Pharma In-Use Search database contains over 400,000 unique pharmaceutical trademarks and trade names that are used in about 50 countries worldwide. The data is provided under license by IMS HEALTH.

11. Natural Medicines Comprehensive Databases (www.naturaldatabase.com) Natural Medicines contains up-to-date clinical data on the natural medicines, herbal medicines, and dietary supplements used in the western world.

12. Stat!Ref (www.statref.com) Stat!Ref contains full-text information from approximately 30 texts; it includes tables and references. Among the database titles are: Handbook of Adverse Drug Interactions, Rudolphs Pediatrics, Basic Clinical Pharmacology, and Dictionary of Medical Acronyms Abbreviations.

13. USAN Stems (http://www.ama-assn.org/ama/pub/category/4782.html) USAN Stems List contains all the recognized USAN stems.

14. Red Book Pharmacy’s Fundamental Reference Red Book contains prices and product information for prescription, over-the-counter drugs, medical devices, and accessories.

15. Lexi-Comp (www.lexi.com) Lexi-Comp is a web-based searchable version of the Drug Information Handbook.

16. Medical Abbreviations Book Medical Abbreviations Book contains commonly used medical abbreviations and their definitions

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APPENDICES Appendix A: FDA’s Proprietary Name Risk Assessment considers the potential for confusion between the proposed proprietary name and the proprietary and established names of drug products existing in the marketplace and those pending IND, NDA, BLA, and ANDA products currently under review by the Center. DMEPA defines a medication error as any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional, patient, or consumer. 3 For the proposed proprietary name, DMEPA staff search a standard set of databases and information sources to identify names with orthographic and phonetic similarity and hold a Center for Drug Evaluation and Research (CDER) Expert Panel discussion to gather professional opinions on the safety of the proposed proprietary name. DMEPA staff also conducts internal CDER prescription analysis studies. When provided, DMEPA considers external prescription analysis study results and incorporate into the overall risk assessment. The Safety Evaluator assigned to the Proprietary Name Risk Assessment is responsible for considering the collective findings, and provides an overall risk assessment of the proposed proprietary name. DMEPA bases the overall risk assessment on the findings of a Failure Mode and Effects Analysis (FMEA) of the proprietary name, and focuses on the avoidance of medication errors. FMEA is a systematic tool for evaluating a process and identifying where and how it might fail. 4 DMEPA uses FMEA to analyze whether the drug names identified with orthographic or phonetic similarity to the proposed proprietary name could cause confusion that subsequently leads to medication errors in the clinical setting. DMEPA uses the clinical expertise of its staff to anticipate the conditions of the clinical setting where the product is likely to be used based on the characteristics of the proposed product. In addition, the product characteristics provide the context for the verbal and written communication of the drug names and can interact with the orthographic and phonetic attributes of the names to increase the risk of confusion when there is overlap or, in some instances, decrease the risk of confusion by helping to differentiate the products through dissimilarity. Accordingly, the DMEPA staff considers the product characteristics associated with the proposed drug throughout the risk assessment because the product characteristics of the proposed may provide a context for communication of the drug name and ultimately determine the use of the product in the usual clinical practice setting. Typical product characteristics considered when identifying drug names that could potentially be confused with the proposed proprietary name include, but are not limited to; established name of the proposed product, proposed indication of use, dosage form, route of administration, strength, unit of measure, dosage units, recommended dose, typical quantity or volume, frequency of administration, product packaging, storage conditions, patient population, and prescriber population. Because drug name confusion can occur at any point in the medication use process, DMEPA staff considers the potential for confusion throughout the entire U.S. medication use

3 National Coordinating Council for Medication Error Reporting and Prevention. http://www.nccmerp.org/aboutMedErrors.html. Last accessed 10/11/2007. 4 Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. IHI:2004.

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process, including drug procurement, prescribing and ordering, dispensing, administration, and monitoring the impact of the medication.5 DMEPA provides the product characteristics considered for this review in section one. The Division of Medication Error Prevention and Analysis considers the spelling of the name, pronunciation of the name when spoken, and appearance of the name when scripted. DMEPA also compares the spelling of the proposed proprietary name with the proprietary and established name of existing and proposed drug products because similarly in spelled names may have greater likelihood to sound similar to one another when spoken or look similar to one another when scripted. DMEPA staff also examines the orthographic appearance of the proposed name using a number of different handwriting samples. Handwritten communication of drug names has a long-standing association with drug name confusion. Handwriting can cause similarly and even dissimilarly spelled drug name pairs to appear very similar to one another. The similar appearance of drug names when scripted has led to medication errors. The DMEPA staff applies expertise gained from root-cause analysis of such medication errors to identify sources of ambiguity within the name that could be introduced when scripting (e.g.,“T” may look like “F,” lower case ‘a’ looks like a lower case ‘u,’ etc). Additionally, other orthographic attributes that determine the overall appearance of the drug name when scripted (see Table 1 below for details). In addition, the DMEPA staff compares the pronunciation of the proposed proprietary name with the pronunciation of other drug names because verbal communication of medication names is common in clinical settings. If provided, DMEPA will consider the Applicant’s intended pronunciation of the proprietary name. However, DMEPA also considers a variety of pronunciations that could occur in the English language because the Applicant has little control over how the name will be spoken in clinical practice. Table 1. Criteria used to identify drug names that look- or sound-similar to a proposed proprietary name. Considerations when searching the databases Type of Potential causes Attributes examined to identify Potential Effects similarity of drug name similar drug names similarity Identical prefix • Similar spelling Names may appear similar Identical infix in print or electronic media Identical suffix and lead to drug name Length of the name confusion in printed or Overlapping product characteristics electronic communication • Names may look similar when scripted and lead to drug name confusion in Look- written communication Similar spelling • alike Orthographic Names may look similar Length of the name similarity when scripted, and lead to Upstrokes drug name confusion in Down strokes written communication Cross-strokes Dotted letters

5 Institute of Medicine. Preventing Medication Errors. The National Academies Press: Washington DC. 2006.

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Ambiguity introduced by scripting letters Overlapping product characteristics Identical prefix • Sound- Phonetic similarity Names may sound similar Identical infix when pronounced and lead alike Identical suffix to drug name confusion in Number of syllables verbal communication Stresses Placement of vowel sounds Placement of consonant sounds Overlapping product characteristics

Lastly, the DMEPA staff also considers the potential for the proposed proprietary name to inadvertently function as a source of error for reasons other than name confusion. Post-marketing experience has demonstrated that proprietary names (or components of the proprietary name) can be a source of error in a variety of ways. Consequently, DMEPA considers and evaluates these broader safety implications of the name throughout this assessment and the medication error staff provides additional comments related to the safety of the proposed proprietary name or product based on professional experience with medication errors.

1. Database and Information Sources DMEPA staff conducts searches of the internet, several standard published drug product reference texts, and FDA databases to identify existing and proposed drug names that may sound- alike or look-alike to the proposed proprietary name using the criteria outlined in Section 2.1. Section 6 provides a standard description of the databases used in the searches. To complement the process, the DMEPA staff use a computerized method of identifying phonetic and orthographic similarity between medication names. The program, Phonetic and Orthographic Computer Analysis (POCA), uses complex algorithms to select a list of names from a database that have some similarity (phonetic, orthographic, or both) to the trademark being evaluated. Lastly, the DMEPA staff review the USAN stem list to determine if any USAN stems are present within the proprietary name. The individual findings of multiple safety evaluators are pooled and presented to the CDER Expert Panel.

2. CDER Expert Panel Discussion DMEPA conducts an Expert Panel Discussion to gather CDER professional opinions on the safety of the proposed product and the proposed proprietary name. The Expert Panel is composed of Division of Medication Errors Prevention (DMEPA) staff and representatives from the Division of Drug Marketing, Advertising, and Communications (DDMAC). The Expert Panel also discusses potential concerns regarding drug marketing and promotion related to the proposed names. The primary Safety Evaluator presents the pooled results of the DMEPA staff to the Expert Panel for consideration. Based on the clinical and professional experiences of the Expert Panel members, the Panel may recommend the addition of names, additional searches by the primary Safety Evaluator to supplement the pooled results, or general advice to consider when reviewing the proposed proprietary name.

3. FDA Prescription Analysis Studies Three separate studies are conducted within the Centers of the FDA for the proposed proprietary name to determine the degree of confusion of the proposed proprietary name with marketed U.S.

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drug names (proprietary and established) due to similarity in visual appearance with handwritten prescriptions or verbal pronunciation of the drug name. The studies employ healthcare professionals (pharmacists, physicians, and nurses), and attempts to simulate the prescription ordering process. The primary Safety Evaluator uses the results to identify orthographic or phonetic vulnerability of the proposed name to be misinterpreted by healthcare practitioners. In order to evaluate the potential for misinterpretation of the proposed proprietary name in handwriting and verbal communication of the name, inpatient medication orders and/or outpatient prescriptions are written, each consisting of a combination of marketed and unapproved drug products, including the proposed name. These orders are optically scanned and one prescription is delivered to a random sample of the 123 participating health professionals via e-mail. In addition, a verbal prescription is recorded on voice mail. The voice mail messages are then sent to a random sample of the participating health professionals for their interpretations and review. After receiving either the written or verbal prescription orders, the participants send their interpretations of the orders via e-mail to DMEPA.

4. Safety Evaluator Risk Assessment of the Proposed Proprietary Name The primary Safety Evaluator applies his/her individual expertise gained from evaluating medication errors reported to FDA, conducts a Failure Mode and Effects Analysis, and provides an overall risk assessment of name confusion. Failure Mode and Effects Analysis (FMEA) is a systematic tool for evaluating a process and identifying where and how it might fail.6 When applying FMEA to assess the risk of a proposed proprietary name, DMEPA seeks to evaluate the potential for a proposed proprietary name to be confused with another drug name because of name confusion and, thereby, cause errors to occur in the medication use system. FMEA capitalizes on the predictable and preventable nature of medication errors associated with drug name confusion. FMEA allows the Agency to identify the potential for medication errors due to orthographically or phonetically similar drug names prior to approval, where actions to overcome these issues are easier and more effective than remedies available in the post-approval phase. In order to perform an FMEA of the proposed name, the primary Safety Evaluator must analyze the use of the product at all points in the medication use system. Because the proposed product is has not been marketed, the primary Safety Evaluator anticipates the use of the product in the usual practice settings by considering the clinical and product characteristics listed in Section one. The Safety Evaluator then analyzes the proposed proprietary name in the context of the usual practice setting and works to identify potential failure modes and the effects associated with the failure modes. In the initial stage of the Risk Assessment, the Safety Evaluator compares the proposed proprietary name to all of the names gathered from the above searches, Expert Panel Discussion, and prescription studies, external studies, and identifies potential failure modes by asking: “Is the proposed proprietary name convincingly similar to another drug name, which may cause practitioners to become confused at any point in the usual practice setting?” An affirmative answer indicates a failure mode and represents a potential for the proposed proprietary name to be confused with another proprietary or established drug name because of look- or sound-alike similarity. If the answer to the question is no, the Safety Evaluator is not convinced that the names posses similarity that would cause confusion at any point in the medication use system, thus the name is eliminated from further review.

6 Institute for Healthcare Improvement (IHI). Failure Mode and Effects Analysis. Boston. IHI:2004.

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In the second stage of the Risk Assessment, the primary Safety Evaluator evaluates all potential failure modes to determine the likely effect of the drug name confusion, by asking: “Could the confusion of the drug names conceivably result in medication errors in the usual practice setting?” The answer to this question is a central component of the Safety Evaluator’s overall risk assessment of the proprietary name. If the Safety Evaluator determines through FMEA that the name similarity would not ultimately be a source of medication errors in the usual practice setting, the primary Safety Evaluator eliminates the name from further analysis. However, if the Safety Evaluator determines through FMEA that the name similarity could ultimately cause medication errors in the usual practice setting, the Safety Evaluator will then recommend the use of an alternate proprietary name. DMEPA will object to the use of proposed proprietary name when the primary Safety Evaluator identifies one or more of the following conditions in the Risk Assessment: a. DDMAC finds the proposed proprietary name misleading from a promotional perspective, and the Review Division concurs with DDMAC’s findings. The Federal Food, Drug, and Cosmetic Act provides that labeling or advertising can misbrand a product if misleading representations are made or suggested by statement, word, design, device, or any combination thereof, whether through a PROPRIETARY name or otherwise [21 U.S.C 321(n); See also 21 U.S.C. 352(a) & (n)]. b. DMEPA identifies that the proposed proprietary name is misleading because of similarity in spelling or pronunciation to another proprietary or established name of a different drug or ingredient [CFR 201.10.(C)(5)]. c. FMEA identifies the potential for confusion between the proposed proprietary name and other proprietary or established drug name(s), and demonstrates that medication errors are likely to result from the drug name confusion under the conditions of usual clinical practice. d. The proposed proprietary name contains an USAN (United States Adopted Names) stem. e. DMEPA identifies a potential source of medication error within the proposed proprietary name. For example, the proprietary name may be misleading or, inadvertently, introduce ambiguity and confusion that leads to errors. Such errors may not necessarily involve confusion between the proposed drug and another drug product. If DMEPA objects to a proposed proprietary name on the basis that drug name confusion could lead to medication errors, the primary Safety Evaluator uses the FMEA process to identify strategies to reduce the risk of medication errors. DMEPA is likely to recommend that the Applicant select an alternative proprietary name and submit the alternate name to the Agency for DMEPA to review. However, in rare instances FMEA may identify plausible strategies that could reduce the risk of medication error of the currently proposed name. In that instance, DMEPA may be able to provide the Applicant with recommendations that reduce or eliminate the potential for error and, thereby, would render the proposed name acceptable. In the event that DMEPA objects to the use of the proposed proprietary name, based upon the potential for confusion with another proposed (but not yet approved) proprietary name, DMEPA will provide a contingency objection based on the date of approval. Whichever product, the Agency approves first has the right to use the proprietary name, while DMEPA will recommend that the second product to reach approval seek an alternative name. The threshold set for objection to the proposed proprietary name may seem low to the Applicant. However, the safety concerns set forth in criteria a through e are supported either

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------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. ------/s/ ------DENISE V BAUGH 10/08/2010

TODD D BRIDGES 10/08/2010

DENISE P TOYER 10/08/2010

CAROL A HOLQUIST 10/08/2010

Reference ID: 2847314